The rostral ventral medulla (RVM) has been implicated in the descending modulation of pain. The RVM is enriched in mu-, delta- and kappa opioid receptors. Systemic opioid agonist administration of infusion of these agents directly into the RVM produces antinociception. The selective blockade of opioid receptors in the RVM attenuates the analgesic effect of systemically administered opiates indicating that activation of opioid receptors in this brain region is both sufficient and necessary for the production of antinociception.[unreadable] [unreadable] Previous work has shown that the analgesic effects produced by supraspinal infusion of mu and delta opioid receptor agonists are potentiated during persistent inflammation. Whether this potentiation extends to other stimulus modalities or to kappa opioid receptor agonists is unknown. To examine these issues, rats received a unilateral intraplantar injection of complete Freund's adjuvant. Antinociception produced by RVM infusion of the kappa opioid receptor agonist, U69593, and the mu opioid receptor agonist, DAMGO, was tested 4h-2 weeks thereafter by assessing thermal paw withdrawal latencies and mechanical thresholds of the inflammed and non-inflammed hindlimb. Withdrawal latencies and mechanical thresholds of the inflamed paw were reduced for at least 2 weeks after the induction of inflammation. Infusion of either U69593 or DAMGO increased withdrawal latencies of the inflammed and non-inflammed hindlimb. A bilateral enhancement of the response to both agonists was observed 2 weeks relative to 4h post-CFA injection. Agonist infusion also elevated mechanical thresholds of the inflamed and non-inflamed paws. The magnitude of the DAMGO effect was greater 2 weeks after the induction of inflammation whereas the effects of U69593 increased progressively as a function of the duration of inflammation. These data demonstrate that RVM infusion of mu- or kappa agonists attenuates thermal and tactile allodynia and that these effects increase during prolonged inflammation. The augmented response of the non-inflamed paw to agonists suggests that inflammation induces centrally-mediated neuroplastic changes which enhances antinociception. [unreadable] [unreadable] GABAergic and glutamatergic signaling has been implicated in mediating RVM-mediated opiate antinociception. Infusion of GABA receptor antagonists into the RVM produces analgesia. Infusion of glutamate into this region produces simlar effects. Analgesia produced by systemic morphine administration can be prevented by RVM administration of GABA-A receptor agonists or non-selective excitatory amino acid receptor antagonists Whole cell patch clamp recordings in RVM slices have provided functional evidence that mu-opioid receptor activation modulate the release of inhibitory and excitatory neurotransmitters onto spinally projecting neurons Although these data suggest that GABAergic signaling is altered in the RVM during mu-opioid receptor mediated analgesia, studies directly assessing mu-opioid receptor agonist evoked changes in glutamate and GABA release in the behaving animal are lacking. [unreadable] [unreadable] We used in vivo microdialysis to investigate this issue. Local perfusion of the selective mu-opioid receptor agonist, DAMGO, produced a concentration-dependent decrease of GABA release in the RVM. Behavioral testing revealed that only concentrations of DAMGO that decreased GABA levels increased thermal withdrawal thresholds. DAMGO did not alter glutamate concentrations in microdialysates. Addition of KCl (60 mM) was also without effect. Since rapid, transporter-mediated uptake may mask detection of changes in glutamate release, the selective excitatory amino acid transporter inhibitor pyrrolidine-2,4-dicarboxylic acid (tPDC) was added to the perfusion medium for subsequent studies. tPDC increased glutamate concentrations, confirming transport inhibition. KCl increased microdialysate levels of gluatame in the presence of tPDC demonstratting that transport inhibition permits detection of depolarization-evoked glutamate release. In the presence of tPDC, DAMGO increased glutamate levels in a concentration-dependent manner. These data provide the first direct demonstration that mu opioid receptor activation decreases GABA and increases glutamate release in the RVM. We hypothesize that the opposing effects of mu-opioid receptor activation on glutamate and GABA transmission contribute to opiate antinociception.[unreadable] [unreadable] In view of the role of glutamate transmission in nociceptive processing and opiate antinociception, we have initiated studies to determine whether a novel family of proteins that involved in the post-synaptic regulation of glutamate function are altered in response to nerve injury and inflammation and whether manipulations that affect their activity can modulate the thermal and mechanical hypersensitivity. hyperalgesia. Using animal models of peripheral neuropathy, we have found that manipulations that decrease protein activity significantly attenuate the development and expression of nerve-injury evoked mechanical hyperalgesia and allodynia. These manipulations are also effective in modulating the hyperalgesia and tactile allodynia that occur following persistent inflammation. On-going studies are examining whether targeting these proteins can attenuate diabetic and retroviral therapy-associated peripheral neuropathy.